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. 1995 Jul 2;130(2):407–418. doi: 10.1083/jcb.130.2.407

Expression of Notch 1, 2 and 3 is regulated by epithelial-mesenchymal interactions and retinoic acid in the developing mouse tooth and associated with determination of ameloblast cell fate

PMCID: PMC2199945  PMID: 7615640

Abstract

Notch 1, Notch 2, and Notch 3 are three highly conserved mammalian homologues of the Drosophila Notch gene, which encodes a transmembrane protein important for various cell fate decisions during development. Little is yet known about regulation of mammalian Notch gene expression, and this issue has been addressed in the developing rodent tooth during normal morphogenesis and after experimental manipulation. Notch 1, 2, and 3 genes show distinct cell-type specific expression patterns. Most notably, Notch expression is absent in epithelial cells in close contact with mesenchyme, which may be important for acquisition of the ameloblast fate. This reveals a previously unknown prepatterning of dental epithelium at early stages, and suggests that mesenchyme negatively regulates Notch expression in epithelium. This hypothesis has been tested in homo- and heterotypic explant experiments in vitro. The data show that Notch expression is downregulated in dental epithelial cells juxtaposed to mesenchyme, indicating that dental epithelium needs a mesenchyme-derived signal in order to maintain the downregulation of Notch. Finally, Notch expression in dental mesenchyme is upregulated in a region surrounding beads soaked in retinoic acid (50-100 micrograms/ml) but not in fibroblast growth factor-2 (100-250 micrograms/ml). The response to retinoic acid was seen in explants of 11-12-d old mouse embryos but not in older embryos. These data suggest that Notch genes may be involved in mediating some of the biological effects of retinoic acid during normal development and after teratogenic exposure.

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Selected References

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  1. Adams J. C., Watt F. M. Regulation of development and differentiation by the extracellular matrix. Development. 1993 Apr;117(4):1183–1198. doi: 10.1242/dev.117.4.1183. [DOI] [PubMed] [Google Scholar]
  2. Artavanis-Tsakonas S., Delidakis C., Fehon R. G. The Notch locus and the cell biology of neuroblast segregation. Annu Rev Cell Biol. 1991;7:427–452. doi: 10.1146/annurev.cb.07.110191.002235. [DOI] [PubMed] [Google Scholar]
  3. Artavanis-Tsakonas S., Simpson P. Choosing a cell fate: a view from the Notch locus. Trends Genet. 1991 Nov-Dec;7(11-12):403–408. doi: 10.1016/0168-9525(91)90264-q. [DOI] [PubMed] [Google Scholar]
  4. Bloch-Zupan A., Décimo D., Loriot M., Mark M. P., Ruch J. V. Expression of nuclear retinoic acid receptors during mouse odontogenesis. Differentiation. 1994 Sep;57(3):195–203. doi: 10.1046/j.1432-0436.1994.5730195.x. [DOI] [PubMed] [Google Scholar]
  5. Coffman C. R., Skoglund P., Harris W. A., Kintner C. R. Expression of an extracellular deletion of Xotch diverts cell fate in Xenopus embryos. Cell. 1993 May 21;73(4):659–671. doi: 10.1016/0092-8674(93)90247-n. [DOI] [PubMed] [Google Scholar]
  6. Corbin V., Michelson A. M., Abmayr S. M., Neel V., Alcamo E., Maniatis T., Young M. W. A role for the Drosophila neurogenic genes in mesoderm differentiation. Cell. 1991 Oct 18;67(2):311–323. doi: 10.1016/0092-8674(91)90183-y. [DOI] [PubMed] [Google Scholar]
  7. Couwenhoven R. I., Snead M. L. Early determination and permissive expression of amelogenin transcription during mouse mandibular first molar development. Dev Biol. 1994 Jul;164(1):290–299. doi: 10.1006/dbio.1994.1199. [DOI] [PubMed] [Google Scholar]
  8. Cummings C. A., Cronmiller C. The daughterless gene functions together with Notch and Delta in the control of ovarian follicle development in Drosophila. Development. 1994 Feb;120(2):381–394. doi: 10.1242/dev.120.2.381. [DOI] [PubMed] [Google Scholar]
  9. Ellisen L. W., Bird J., West D. C., Soreng A. L., Reynolds T. C., Smith S. D., Sklar J. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell. 1991 Aug 23;66(4):649–661. doi: 10.1016/0092-8674(91)90111-b. [DOI] [PubMed] [Google Scholar]
  10. Fehon R. G., Kooh P. J., Rebay I., Regan C. L., Xu T., Muskavitch M. A., Artavanis-Tsakonas S. Molecular interactions between the protein products of the neurogenic loci Notch and Delta, two EGF-homologous genes in Drosophila. Cell. 1990 May 4;61(3):523–534. doi: 10.1016/0092-8674(90)90534-l. [DOI] [PubMed] [Google Scholar]
  11. Fortini M. E., Artavanis-Tsakonas S. Notch: neurogenesis is only part of the picture. Cell. 1993 Dec 31;75(7):1245–1247. doi: 10.1016/0092-8674(93)90611-s. [DOI] [PubMed] [Google Scholar]
  12. Fortini M. E., Rebay I., Caron L. A., Artavanis-Tsakonas S. An activated Notch receptor blocks cell-fate commitment in the developing Drosophila eye. Nature. 1993 Oct 7;365(6446):555–557. doi: 10.1038/365555a0. [DOI] [PubMed] [Google Scholar]
  13. Geelen J. A. Hypervitaminosis A induced teratogenesis. CRC Crit Rev Toxicol. 1979 Nov;6(4):351–375. doi: 10.3109/10408447909043651. [DOI] [PubMed] [Google Scholar]
  14. Greenwald I. Structure/function studies of lin-12/Notch proteins. Curr Opin Genet Dev. 1994 Aug;4(4):556–562. doi: 10.1016/0959-437x(94)90072-b. [DOI] [PubMed] [Google Scholar]
  15. Jernvall J., Kettunen P., Karavanova I., Martin L. B., Thesleff I. Evidence for the role of the enamel knot as a control center in mammalian tooth cusp formation: non-dividing cells express growth stimulating Fgf-4 gene. Int J Dev Biol. 1994 Sep;38(3):463–469. [PubMed] [Google Scholar]
  16. Jhappan C., Gallahan D., Stahle C., Chu E., Smith G. H., Merlino G., Callahan R. Expression of an activated Notch-related int-3 transgene interferes with cell differentiation and induces neoplastic transformation in mammary and salivary glands. Genes Dev. 1992 Mar;6(3):345–355. doi: 10.1101/gad.6.3.345. [DOI] [PubMed] [Google Scholar]
  17. Jowett A. K., Vainio S., Ferguson M. W., Sharpe P. T., Thesleff I. Epithelial-mesenchymal interactions are required for msx 1 and msx 2 gene expression in the developing murine molar tooth. Development. 1993 Feb;117(2):461–470. doi: 10.1242/dev.117.2.461. [DOI] [PubMed] [Google Scholar]
  18. Kessel M., Gruss P. Homeotic transformations of murine vertebrae and concomitant alteration of Hox codes induced by retinoic acid. Cell. 1991 Oct 4;67(1):89–104. doi: 10.1016/0092-8674(91)90574-i. [DOI] [PubMed] [Google Scholar]
  19. Kollar E. J., Baird G. R. The influence of the dental papilla on the development of tooth shape in embryonic mouse tooth germs. J Embryol Exp Morphol. 1969 Feb;21(1):131–148. [PubMed] [Google Scholar]
  20. Kronmiller J. E., Beeman C. S., Kwiecien K., Rollins T. Effects of the intermediate retinoid metabolite retinal on the pattern of the dental lamina in vitro. Arch Oral Biol. 1994 Oct;39(10):839–845. doi: 10.1016/0003-9969(94)90015-9. [DOI] [PubMed] [Google Scholar]
  21. Lardelli M., Dahlstrand J., Lendahl U. The novel Notch homologue mouse Notch 3 lacks specific epidermal growth factor-repeats and is expressed in proliferating neuroepithelium. Mech Dev. 1994 May;46(2):123–136. doi: 10.1016/0925-4773(94)90081-7. [DOI] [PubMed] [Google Scholar]
  22. Larsson C., Lardelli M., White I., Lendahl U. The human NOTCH1, 2, and 3 genes are located at chromosome positions 9q34, 1p13-p11, and 19p13.2-p13.1 in regions of neoplasia-associated translocation. Genomics. 1994 Nov 15;24(2):253–258. doi: 10.1006/geno.1994.1613. [DOI] [PubMed] [Google Scholar]
  23. Lumsden A. G. Spatial organization of the epithelium and the role of neural crest cells in the initiation of the mammalian tooth germ. Development. 1988;103 (Suppl):155–169. doi: 10.1242/dev.103.Supplement.155. [DOI] [PubMed] [Google Scholar]
  24. Löwenadler B., Jansson B., Paleus S., Holmgren E., Nilsson B., Moks T., Palm G., Josephson S., Philipson L., Uhlén M. A gene fusion system for generating antibodies against short peptides. Gene. 1987;58(1):87–97. doi: 10.1016/0378-1119(87)90032-1. [DOI] [PubMed] [Google Scholar]
  25. MacKenzie A., Ferguson M. W., Sharpe P. T. Expression patterns of the homeobox gene, Hox-8, in the mouse embryo suggest a role in specifying tooth initiation and shape. Development. 1992 Jun;115(2):403–420. doi: 10.1242/dev.115.2.403. [DOI] [PubMed] [Google Scholar]
  26. Mackenzie A., Leeming G. L., Jowett A. K., Ferguson M. W., Sharpe P. T. The homeobox gene Hox 7.1 has specific regional and temporal expression patterns during early murine craniofacial embryogenesis, especially tooth development in vivo and in vitro. Development. 1991 Feb;111(2):269–285. doi: 10.1242/dev.111.2.269. [DOI] [PubMed] [Google Scholar]
  27. Marshall H., Nonchev S., Sham M. H., Muchamore I., Lumsden A., Krumlauf R. Retinoic acid alters hindbrain Hox code and induces transformation of rhombomeres 2/3 into a 4/5 identity. Nature. 1992 Dec 24;360(6406):737–741. doi: 10.1038/360737a0. [DOI] [PubMed] [Google Scholar]
  28. Mina M., Kollar E. J. The induction of odontogenesis in non-dental mesenchyme combined with early murine mandibular arch epithelium. Arch Oral Biol. 1987;32(2):123–127. doi: 10.1016/0003-9969(87)90055-0. [DOI] [PubMed] [Google Scholar]
  29. Mitsiadis T. A., Dicou E., Joffre A., Magloire H. Immunohistochemical localization of nerve growth factor (NGF) and NGF receptor (NGF-R) in the developing first molar tooth of the rat. Differentiation. 1992 Jan;49(1):47–61. doi: 10.1111/j.1432-0436.1992.tb00768.x. [DOI] [PubMed] [Google Scholar]
  30. Mitsiadis T. A., Luukko K. Neurotrophins in odontogenesis. Int J Dev Biol. 1995 Feb;39(1):195–202. [PubMed] [Google Scholar]
  31. Mitsiadis T. A., Muramatsu T., Muramatsu H., Thesleff I. Midkine (MK), a heparin-binding growth/differentiation factor, is regulated by retinoic acid and epithelial-mesenchymal interactions in the developing mouse tooth, and affects cell proliferation and morphogenesis. J Cell Biol. 1995 Apr;129(1):267–281. doi: 10.1083/jcb.129.1.267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Mitsiadis T. A., Salmivirta M., Muramatsu T., Muramatsu H., Rauvala H., Lehtonen E., Jalkanen M., Thesleff I. Expression of the heparin-binding cytokines, midkine (MK) and HB-GAM (pleiotrophin) is associated with epithelial-mesenchymal interactions during fetal development and organogenesis. Development. 1995 Jan;121(1):37–51. doi: 10.1242/dev.121.1.37. [DOI] [PubMed] [Google Scholar]
  33. Nagpal S., Friant S., Nakshatri H., Chambon P. RARs and RXRs: evidence for two autonomous transactivation functions (AF-1 and AF-2) and heterodimerization in vivo. EMBO J. 1993 Jun;12(6):2349–2360. doi: 10.1002/j.1460-2075.1993.tb05889.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Rebay I., Fehon R. G., Artavanis-Tsakonas S. Specific truncations of Drosophila Notch define dominant activated and dominant negative forms of the receptor. Cell. 1993 Jul 30;74(2):319–329. doi: 10.1016/0092-8674(93)90423-n. [DOI] [PubMed] [Google Scholar]
  35. Rebay I., Fleming R. J., Fehon R. G., Cherbas L., Cherbas P., Artavanis-Tsakonas S. Specific EGF repeats of Notch mediate interactions with Delta and Serrate: implications for Notch as a multifunctional receptor. Cell. 1991 Nov 15;67(4):687–699. doi: 10.1016/0092-8674(91)90064-6. [DOI] [PubMed] [Google Scholar]
  36. Robbins J., Blondel B. J., Gallahan D., Callahan R. Mouse mammary tumor gene int-3: a member of the notch gene family transforms mammary epithelial cells. J Virol. 1992 Apr;66(4):2594–2599. doi: 10.1128/jvi.66.4.2594-2599.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Satokata I., Maas R. Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development. Nat Genet. 1994 Apr;6(4):348–356. doi: 10.1038/ng0494-348. [DOI] [PubMed] [Google Scholar]
  38. Struhl G., Fitzgerald K., Greenwald I. Intrinsic activity of the Lin-12 and Notch intracellular domains in vivo. Cell. 1993 Jul 30;74(2):331–345. doi: 10.1016/0092-8674(93)90424-o. [DOI] [PubMed] [Google Scholar]
  39. Swiatek P. J., Lindsell C. E., del Amo F. F., Weinmaster G., Gridley T. Notch1 is essential for postimplantation development in mice. Genes Dev. 1994 Mar 15;8(6):707–719. doi: 10.1101/gad.8.6.707. [DOI] [PubMed] [Google Scholar]
  40. Tabin C. J. Retinoids, homeoboxes, and growth factors: toward molecular models for limb development. Cell. 1991 Jul 26;66(2):199–217. doi: 10.1016/0092-8674(91)90612-3. [DOI] [PubMed] [Google Scholar]
  41. Thesleff I., Hurmerinta K. Tissue interactions in tooth development. Differentiation. 1981;18(2):75–88. doi: 10.1111/j.1432-0436.1981.tb01107.x. [DOI] [PubMed] [Google Scholar]
  42. Thesleff I., Vaahtokari A., Partanen A. M. Regulation of organogenesis. Common molecular mechanisms regulating the development of teeth and other organs. Int J Dev Biol. 1995 Feb;39(1):35–50. [PubMed] [Google Scholar]
  43. Tickle C. Retinoic acid and chick limb bud development. Dev Suppl. 1991;1:113–121. [PubMed] [Google Scholar]
  44. Vainio S., Jalkanen M., Thesleff I. Syndecan and tenascin expression is induced by epithelial-mesenchymal interactions in embryonic tooth mesenchyme. J Cell Biol. 1989 May;108(5):1945–1953. doi: 10.1083/jcb.108.5.1945. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Vainio S., Karavanova I., Jowett A., Thesleff I. Identification of BMP-4 as a signal mediating secondary induction between epithelial and mesenchymal tissues during early tooth development. Cell. 1993 Oct 8;75(1):45–58. [PubMed] [Google Scholar]
  46. de Celis J. F., Marí-Beffa M., García-Bellido A. Cell-autonomous role of Notch, an epidermal growth factor homologue, in sensory organ differentiation in Drosophila. Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):632–636. doi: 10.1073/pnas.88.2.632. [DOI] [PMC free article] [PubMed] [Google Scholar]

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